1. Field of the Invention
The present invention relates to processes for dispersing a cohesive high-dosage strength micronized active ingredient in a dry powder formulation for inhalation comprising carrier particles, and an apparatus thereof.
2. Discussion of the Background
The administration of pharmacologically active ingredients by inhalation to the airways is a widely used technique especially for the treatment of reversible airway obstruction, inflammation, and hyper-responsiveness.
Some of the most widely used systems for the administration of drugs to the airways are represented by dry powder inhalers (DPIs) which, in turn, can be divided into two basic types: i) single dose inhalers, for the administration of single subdivided doses of the active compound, each single dose being usually filled in a capsule; and ii) multidose inhalers pre-loaded with quantities of active ingredients sufficient for longer treatment cycles.
Drugs intended for inhalation as dry powders by means of DPIs should be used in the form of micronized particles. Micronization is generally achieved by conventional milling processes known to the skilled person.
Although micronization of the drug is essential for deposition into the lower respiratory tract during inhalation, it is also known that the finer are the particles, the stronger are the cohesion forces among them. Strong cohesion forces hinder the handling of the powder during the manufacturing process (pouring, filling). Moreover they reduce the flowability of the particles, while favoring, inside the multidose DPI's, the agglomeration and the adhesion thereof to the walls of the reservoir. Said phenomena impair the loading of the powder from the reservoir to the metering chamber and, hence, give rise to handling and metering accuracy problems.
Poor flowability is also detrimental to the respirable fraction of the delivered dose in that the active particles are unable to properly leave the inhaler, essentially because they remain adhered to the interior of the inhaler and/or leave the inhaler as large agglomerates; agglomerated particles, in turn, cannot reach the bronchiolar and alveolar sites of the lungs. The uncertainty as to the extent of agglomeration of the particles between each actuation of the inhaler and, also, among inhalers and different batches of particles, leads to poor dose reproducibility as well.
For these reasons, powders for inhalation are commonly formulated by diluting the micronized drug in a pharmacologically inert physiologically acceptable excipient of coarser particles to yield the so-called “interactive ordered mixtures”.
However, it has been found that particularly cohesive active ingredients to be delivered at relatively high doses, e.g. equal to or higher than 100 μg per actuation, are difficult to disperse, and form agglomerates even though they are diluted by mixing with coarse excipient particles.
The presence of the agglomerates leads to problems in the manufacturing of inhalable powder formulations with a good uniformity distribution of the active ingredient in the blend as well as a good dosage reproducibility and high respirable fraction upon administration by DPI's.
In view of the problems outlined above, it would be highly advantageous to provide a process for preparing powder formulations for inhalation comprising cohesive active ingredients to be delivered at high doses per actuation capable of achieving a good dispersion of active particles when properly diluted with coarse carrier particles.
The problem is solved by the process of the present invention.